DESCRIPTION: The long-term goal is to develop advanced, multi-functional neural interfaces for localized interaction with the biological environment. Long-term, intracortical microelectrode array reliability will be maintained through preventing, detecting, and controlling the biological tissue response to the implanted device. To accomplish this goal, microscale intracortical neural interfaces based on materials that seamlessly integrate within the neural tissue will be integrated with microfluidic drug delivery capabilities and neurochemical sensors. Intracortical implants for neural spike recording are hampered by a loss of neural recording quality in the weeks and months after implantation. The neuroinflammatory tissue response leading to glial encapsulation around the implants is widely hypothesized as the cause of the gradual loss of neural spike recording quality. While efforts to extend recording reliability have been made through the use of novel materials to reduce probe-tissue mechanical-mismatch or by delivery of anti-inflammatory agents, a multi-faceted approach to eliminating the neuroinflammatory response is lacking. There is currently no practical technique to track tissue response activity at the implant-tissue interface in situ before encapsulation has occurred, at which point damage to the biotic-abiotic interface may be irreversible. In the absence of an in situ measure of neuroinflammatory activity, therapeutic intervention to temper the tissue response via drug delivery is less effective. This project will use a novel polymer nanocomposite as the implant structural material to prevent the tissue response, a glutamate sensor to detect the tissue response, and microfluidic drug delivery capabilities to control the tissue response. The primary hypothesis of this proposal is that a microfabrication-based approach can be used to integrate a mechanically-adaptive polymer nanocomposite with the functions required for a closed-loop control system for preventing and treating the biological response to neural implants. This research project is divided into two distinct specific aims. The first aim will use electrochemical sensors integrated into intracortical microelectrode devices to evaluate the hypothesis that glutamate is an indicator of tissue response activity. Three sets of multi-modal neural probes with both integrated neural recording electrodes and glutamate electrochemical sensors will be studied: a rigid silicon control, a highly-compliant polymer nanocomposite, and a moderately- compliant polymer nanocomposite. Probes will be implanted in the barrel cortex of Sprague-Dawley rats for either 3 days, 2 weeks, or 16 weeks. Electrochemical impedance, neural recordings, and glutamate measurements will be made regularly throughout the implant duration. Afterward, immunohistochemical (IHC) analysis will be performed on fixed tissue to assess the extent of the tissue response. Impedance, neural spike, and glutamate data will be compared to the IHC data to look for correlations between in vivo measures and the cumulative tissue response. By confirming the hypothesis, a simple analyte will have been identified that can be used to track tissue response and serve as a control signal for a closed-loop tissue response control system. In the second aim, microfluidic drug-delivery capabilities will be integrated into the polymer nanocomposite. The moisture permeability of the mechanically-adaptable polymer nanocomposite will be exploited with the design of permeable-walled microfluidic channels to replenish the storage of pharmacologic agents within the nanocomposite. This will enable for controlled, sustained release of a small amount of anti- inflammatory agents highly localized to the region surrounding the implant. These capabilities can then be combined and integrated with microelectronic systems to sense and control the local neuroinflammatory response.